The awakening of an advanced malignant cancer: An insult to the mitochondrial genome (original) (raw)
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A Review on the Role of Mitochondrial DNA Mutations in Cancer
Medical laboratory sciences, 2021
Mitochondria implement various cellular functions, including energy production through the electron transport chain by oxidative phosphorylation mechanism. These respiratory chains consist of several complexes and protein subunits which are encoded by nuclear and mitochondrial genes. Due to mutation susceptibility and repair limitation, more aberrations have occurred in mitochondrial DNA in comparison to nuclear DNA. Given the fact that mitochondrial DNA lacks introns, mutations almost occur in the coding sequence, which comprises a direct impact on its functions. Emerging evidence indicates that mutations in the mitochondrial DNA led to the production of reactive oxygen species, disrupted apoptosis, and tumor development. Studies reported various somatic and germline variants in mitochondrial DNA related to tumorigenesis. The D-loop region which is the starting point for replication and transcription of mitochondrial DNA is the most prevalent site of somatic mutations in solid tumors. The D-loop mutations also cause copy number variations which are gaining interest in studies of solid tumors including breast cancer, colon cancer, hepatocellular carcinomas, and prostate cancer. Most studies have reported a mitochondrial DNA reduction which subsequently prevents apoptosis and promotes metastasis. The mitochondrial DNA regionspecific haplogroups are also involved in the sequence variations due to processes such as genetic drift and adaptive selection. This review article discusses the biology and function of mitochondria and related genes. By explanation of mitochondrial dysfunction caused by different kinds of alterations, we attempt to elucidate the role of mitochondria in tumorigenesis. Prominently published articles in this field were reviewed and the role of germline and somatic mutations of mitochondrial DNA have been investigated in common cancers.
Genetic Modification of Mitochondrial DNA in Cancer Cells
Indian Journal of Forensic Medicine & Toxicology, 2021
Mitochondria is one of the most energy source in the cells, in addition to DNA encoded to several genes which relatively associated with several disease, researchers proved the role of mitochondrial in energy demand to tumor cells in addition to mitochondrial DNA role in cancer initiation and development. The present review explained different objectives related with the mitochondrial role in tumor incidence ; these included Tumor cells energy demands, Mitochondrial Mutations redundancy and allocation, Genetic disparate natural Selection in Tumor initiation, Mitochondrial Modifications Clinical Translations in Cancer, Association Mitochondria, epigenetics and Cancer and finally Injury of Mitochondria in Cancer. The present review concluded that the most important role of mitochondrial as cells an organelles for energy suppliers to tumor cells metastasis and immorality also the mutations of mtDNA and their role in carcinogenesis were well proved in different cancer types.
Mitochondrial DNA mutations in cancer - from bench to bedside
Mitochondria are cell organelles mostly known for their production of ATP through oxidative phosphorylation. As suggested over 70 years ago by O. Warburg and recently confirmed with molecular techniques, alterations in respiratory activity and mitochondrial DNA appear to be a common feature of malignant cells. Somatic mtDNA mutations have been reported in many types of cancer cells. MtDNA mutation pattern may enhance the specificity of cancer diagnostics, detection and prediction of tumor growth rate and patients’ outcome. Therefore it may be used as a molecular cancer bio-marker. Nevertheless recently published papers list a large number of mitochondrial DNA mutations in many different cancer types, but their role in cell patophysiology remains unsummarized. This review covers the consequences of mitochondrial genes mutations for human cell physiology and proliferation. We underline effects of mtDNA mutation-resulting amino acid changes in the respiratory chain proteins’ structure, and propose changes in mitochondrial protein function. Mutations are critically evaluated and interpreted in the functional context and clinical utility of molecular mitochondrial research is summarized and new perspectives for ‘mitochondrial oncology’ suggested. TABLE OF CONTENTS 1. Abstract 2. Introduction 2.1. MtDNA mutation mechanism 2.2. The role of reactive oxygen species in mitochondrial carcinogenesis 3. D-loop mutations in human cancers 3.1. Consequences for cell physiology 3.2. Clinical implications 4. tRNA genes mutations in human cancers 4.1 Consequences for cell physiology 4.2. Clinical implications 5. rRNA genes mutations 6. OXPHOS complex I genes and human cancer 6.1. Consequences for cell physiology 6.2. Clinical implications 7. OXPHOS complex III genes 7.1. Consequences for cell physiology 8. OXPHOS complex IV genes and human cancer 8.1. Consequences for cell physiology 8.2. Clinical implications 9. OXPHOS complex V genes and human cancers 9.1. Consequences for cell physiology 9.2. Clinical implications 10. Large mtDNA deletions and mtDNA depletion in human cancers 11. OXPHOS genes expression in human cancers 12. Summary and perspectives 13. Acknowledgements 14. References
Mitochondrial DNA mutations in human cancer
Oncogene, 2006
Somatic mitochondrial DNA (mtDNA) mutations have been increasingly observed in primary human cancers. As each cell contains many mitochondria with multiple copies of mtDNA, it is possible that wild-type and mutant mtDNA can co-exist in a state called heteroplasmy. During cell division, mitochondria are randomly distributed to daughter cells. Over time, the proportion of the mutant mtDNA within the cell can vary and may drift toward predominantly mutant or wild type to achieve homoplasmy. Thus, the biological impact of a given mutation may vary, depending on the proportion of mutant mtDNAs carried by the cell. This effect contributes to the various phenotypes observed among family members carrying the same pathogenic mtDNA mutation. Most mutations occur in the coding sequences but few result in substantial amino acid changes raising questions as to their biological consequence. Studies reveal that mtDNA play a crucial role in the development of cancer but further work is required to establish the functional significance of specific mitochondrial mutations in cancer and disease progression. The origin of somatic mtDNA mutations in human cancer and their potential diagnostic and therapeutic implications in cancer are discussed. This review article provides a detailed summary of mtDNA mutations that have been reported in various types of cancer. Furthermore, this review offers some perspective as to the origin of these of mutations, their functional consequences in cancer development, and possible therapeutic implications.
Mitochondrial DNA Variations in Tumors: Drivers or Passengers?
Mitochondrial DNA - New Insights, 2018
Mitochondrial DNA alterations, including point mutations, deletions, inversions and copy number variations, have been widely reported in many age-related degenerative diseases and tumors. However, numerous studies investigating their pathogenic role in cancer have provided inconsistent evidence. Furthermore, biological impacts of mitochondrial DNA variants vary tremendously, depending on the proportion of mutant DNA molecules carried by the neoplastic cells (the so-called heteroplasmy). The recent discovery of inter-genomic crosstalk between nucleus and mitochondria has reinforced the role of mitochondrial DNA variants in perturbing this essential signaling pathway and thus indirectly targeting nuclear genes involved in tumorigenic and invasive phenotype. Therefore, mitochondrial dysfunction is currently considered a crucial hallmark of carcinogenesis as well as a promising target for anticancer therapy. This chapter describes the role of different types of mitochondrial DNA alterations by mainly considering the paradigmatic model of colorectal carcinogenesis and, in particular, it revisits the issue of whether mitochondrial mutations are causative cancer drivers or simply genuine passenger events. The advent of high-throughput next-generation sequencing techniques, as well as the development of genetic and pharmaceutical interventions for the treatment of mitochondrial dysfunction in cancer, are also discussed.
Role of Mitochondrial Mutations in Cancer
Endocrine Pathology, 2006
A role for mitochondria in cancer causation has been implicated through identification of mutations in the mitochondrial DNA (mtDNA) and in nuclear-encoded mitochondrial genes. Although many mtDNA mutations were detected in common tumors, an unequivocal causal link between heritable mitochondrial abnormalities and cancer is provided only by the germ line mutations in the nuclear-encoded genes for succinate dehydrogenase (mitochondrial complex II) and fumarate hydratase (fumarase). The absence of evidence for highly penetrant tumors caused by inherited mtDNA mutations contrasts with the frequent occurrence of mtDNA mutations in many different tumor types. Thus, either the majority of diverse mtDNA mutations observed in tumors are not important for the process of carcinogenesis or that they play a common oncogenic role.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2012
There have been many reports of mitochondrial DNA (mtDNA) mutations associated with human malignancies. We have observed allelic instability in UV-induced cutaneous tumors at the mt-Tr locus encoding the mitochondrial tRNA for arginine. We examined the effects of somatic alterations at this locus by modeling the change in a uniform nuclear background by generating cybrids harboring allelic variation at mt-Tr. We utilized the naturally occurring mtDNA variation at mt-Tr within the BALB/cJ (BALB) and C57BL/6J (B6) strains of Mus musculus to transfer their mitochondria into a mouse ρ 0 cell line that lacked its own mtDNA. The BALB haplotype containing the mt-Tr 9821insA allele produced significant changes in cellular respiration (resulting in lowered ATP production), but increased rates of cellular proliferation in cybrid cells. Furthermore, the mtDNA genotype associated with UV-induced tumors endowed the cybrid cells with a phenotype of resistance to UV-induced apoptosis and enhanced migration and invasion capabilities. These studies support a role for mtDNA changes in cancer.
Mitochondrial DNA and carcinogenesis (Review)
Molecular Medicine Reports, 2012
The role of the mitochondria in the process of carcinogenesis has drawn researchers' attention since the discovery of respiratory deficit in cells, particularly those characterized by rapid proliferation. The deficit was assumed to stimulate further differentiation of the cells and initiate the process of neoplastic transformation. As many as 25-80% of somatic mutations in mitochondrial DNA (mtDNA) are found in various neoplasms. These mutations are considered to trigger the neoplastic transformation through shifts of cell energy resources, an increase in the mitochondrial oxidative stress and modulation of apoptosis. The question arises as to whether the mtDNA mutations precede a neoplasm or whether they are a result of changes and processes that take place during neoplastic proliferation. Contents
Generation, function, and prognostic utility of somatic mitochondrial DNA mutations in cancer
Environmental and Molecular Mutagenesis, 2000
Exciting new studies are increasingly strengthening the link between mitochondrial mutagenesis and tumor progression. Here we provide a comprehensive review and meta-analysis of studies reporting on mitochondrial DNA mutations in common human cancers. We discuss possible mechanisms by which mitochondrial DNA mutations may influence carcinogenesis, outline important caveats for interpreting the detected mutations-particularly differentiating causality from association-and suggest how new mutational assays may help resolve fundamental controversies in the field and delineate the origin and expansion of neoplastic cell lineages. Finally, we discuss the potential clinical utility of mtDNA mutations for improving the sensitivity of early cancer diagnosis, rapidly detecting cancer recurrence, and predicting the disease outcome. Environ.